Amino-substituted benzo(g)pteridine-di-n-oxides

ABSTRACT

4-AMINO - PYRIMIDO - (4,5,B) - QUINOXALINE - 5,10DIOXIDES OF THE FORMULA:   4-(R-NH-),5,10-DI(O=)BENZO(G)PTERIDINE   WHEREIN R IS HYDROGEN, A STRAIGHT OR BRANCHED CHAIN SATURATED OR PARTIALLY UNSATURATED SUBSTITUTED OR UNSUBSTITUTED ALIPHATIC MOIETY OR A SUBSTITUTED OR UNSUBSTITUTED CYCLOALIPHATIC MOIETY, ARE PRODUCED BY REACTING QUINOXALINE-DI-N-OXISE OF THE FORMULA:   1,4-DI(O=),2-((CH3-)2-N-CH=N-),3-(NC-)QUINOXALINE   WITH AN AMINE OF THE GENERAL FORMULA R-NH2, WHEREIN R IS AS DEFINED, ABOVE IN A DILUENT, AT A TEMPERATURE IN THE RANGE OF 20* TO 100* C. THESE COMPOUNDS ARE USEFUL FRO THEIR ANTIOMICROBIAL ACTIVITY. THEY EXHIBIT ACTIVITY AGAINST BOTH GRAM POSITIVE AND GRAM NEGATIVE BACTERIA.

United States Patent 3,793,323 AMINO-SUBSTITUTED BENZO(g) PTERIDINE-di-N-OXIDES Florin Seug, Cologne, Kurt Ley, Odenthal-Globusch, and Karl Georg Metzger, Wuppertal-Elberfeld, Germany, as-

signors to Farbenfabriken Bayer Aktieugesellschaft,

Leverkusen, Germany No Drawing. Filed July 7, 1971, Ser. No. 160,542 Claims priority, application Germany, July 11, 1970, P 20 34 467.7 Int. Cl. C07d 57/28 US. Cl. 260-251.5 14 Claims ABSTRACT OF THE DISCLOSURE 4-amino pyrimido (4,5,b) quinoxaline 5,10 dioxides of the formula:

wherein R is hydrogen, a straight or branched chain saturated or partially unsaturated substituted or unsub stituted aliphatic moiety or a substituted or unsubstituted cycloaliphatic moiety, are produced by reacting quinoxaline-di-N-oxide of the formula:

with an amine of the general formula RNH wherein R is as defined, above, in a diluent, at a temperature in the range of 20 to 100 C. These compounds are useful for their antimicrobial activity. They exhibit activity against both gram positive and gram negative bacteria.

H 2 N R N A -L O I wherein R is hydrogen, a straight or branched chain saturated or partially unsaturated, substituted or unsubstituted aliphatic moiety or a substituted or unsubstitued cycloaliphatic moiety.

3,793,323 Patented Feb. 19, 1974 The componds are produced by reacting quinoxalinedi-N-oxide of the Formula II:

CN cm N=OH-N/ il. CH:

with an amine of the Formula III: 1

R NH,

wherein R is as above defined, in a diluent, at a temperature range of from 20 to 100 C.

When R is an aliphatic moiety, it is preferably straight or branched chain alkyl of 1 to 6 carbon atoms, especially 1 to 4 carbon atoms or lower alkenyl of 2 to 6 carbon atoms, especially 2 to 4 carbon atoms.

When R is a cycloaliphatic moiety, it is preferably of 5 to 7 carbon atoms, especially 5 or 6 carbon atoms. Cycloalkyl of 5 to 7 carbon atoms and particularly 5 or 6 carbon atoms is preferred.

When the aliphatic or cycloaliphatic moiety R is substituted, the preferred substituents are one or more, identical or different, preferably one, hydroxyl, alkoxy and/or dialkylamino moiety, wherein the alkoxy portion is of 1 to 4 carbon atoms and preferably 1 or 2 carbon atoms, and the dialkylamino moiety is of 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms in each alkyl moiety.

Examples of R include methyl, ethyl, nand iso-propyl, n-, isoand tert.-butyl, cyclohexyl, allyl, Z-hydroxyethyl, Z-methoxyethyl and l-dimethylaminopropyl.

At least 1 mol of amine or ammonia (HI) is employed per mol of quinoxaline-di-N-oxide (II) in the production of Compounds I, and if desired an excess of amine or ammonia can be used. Preferably 1 to 5, especially 1.5 to 3, mols of amine or ammonia (III) are used per mol of N-oxide (II).

As aliphatic amines (HI) there may be used straight or branched chain alkylamines of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, or alkenylamines of 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. The alkylamines and alkenyl-amines are unsubstituted or substituted by one or more, identical or different, preferably one, of the moieties set forth as substituents for the aliphatic and cycloaliphatic moieties above.

The cycloaliphatic amines (III) are of 5 to 7 carbon atoms, preferably 5 to 6 carbon atoms, and are unsubstituted or substituted by one or more, identical or different, preferably one, of the moieties set forth as substituents for the aliphatic and cycloaliphatic moieties above.

Examples of compounds R-NH (III) include: methylamine, ethylamine, nand iso-propylamine, n-, isoand tert.-butylamine, cyclohexylaimne, allylamine, 2-hydroxyethylamine, Z-methoxyethylamine, l-dimethylamino-propylamine and ammonia.

Ammonia and the other amines (III) can, where convenient or desired, be employed in the gaseous form, but can also be employed in the form of their aqueous solutions.

The preferred temperature range for the reaction between the Compounds II and III is 40 to C.

Suitable diluents or solvents for the reaction are inert organic solvents, especially polar organic solvents, such as, for example, formamide, dimethylformamide and N- methyl-pyrrolidone; lower aliphatic alcohols with, preferably, 1 to 4 carbon atoms, such as, for example, methanol, ethanol, propanol, isopropanol and n-, isoand tert.- butanol; lower alkylnitriles, such as, for example, acetonitrile; ethers, such as, for example, dioxane and tetrahydrofuran; and pyridine.

In detail, the reaction according to the invention may be carried out as follows:

The quinoxaline-di-N-oxide (II) is suspended in one of the above-mentioned diluents and is treated with at least the equivalent quantity of a primary amine or ammonia (III). After warming the mixture to between about 20 and about 100 C., the reaction is complete after about 1 to 5 hours. The reaction product separates out as crystals and may be isolated according to customary methods.

The reaction according to the invention produces, smoothly and in good yields, compounds of the Formula I, which, because of their excellent antimicrobial activity,

4 can be employed in human medicine and veterinary medicine and as fodder additives.

The following examples more particularly illustrate the production of the new compounds according to the present invention.

EXAMPLE 1 HN-Cl-Ia -18 g. (74% of theory) of 4-methylamino-pyrimido-(4,5-b)- quinoxaline-5,10-dioxide are obtained in the form of red crystals which, after recrystallization from dimethylformamide, melt at 189 C., with decomposition.

Analysis.C H N O (243): Calculated (percent): C,

54.3; H, 3.7; N, 28.8. Found (percent): C, 54.1; H, 3.9; N, 28.9.

The following compounds are prepared by methods analogous to that described above by reacting the quinoxaline-di-N-oxide (II) with the amine listed below.

EXAMPLES 28 Reaction Yield Time 'Iem era- M.P. (percent of Formula Amineused (hours) tnre (0 C.) (0C.) theory) 2 (r) HN-CzHs Ethylamine 1 77 N \A l N \N/ 3 (T) 11NCnH-1 Propylamine 5 50 166 64 N A J l O 4 CH Isopropylamine.-. 4 50 172 74 (1? liiN-CH N MA 1 0 5 ZEN-04H; n-Butylamine. 3 60 174 68 A l O 6 Cyclohexylamlne- 3 60 59 (T) HN N N EXAMPLES 2-8-Continued Reaction Yield Time Tem era- M.P. (percent of Formula Amine used (hours) ture 0.) (0 C.) theory) 7 (T) HN-CHa-CH2OH Ethanolamine....- 1 70 1 174 64 8....-- (T) NH: Ammonia 8 60 300 88 N x 1 C ie N) l O l Decomposition.

The di-N-oxide (11) used as starting material is obtained from 2-amino-3-cyano-quinoxaline-di-N-oxide and diggi figfl ggff methylformamide in the presence of phosphorus oxychlo- C d if E ride, in the following manner. 31 53;? om mp1s 7 3 5 2 1 6 4 O Escherichia coli A 261 T Escherichia coli 0 165 N Proteus oulgaris" CN Pseud monas aeru Cm Klebsiella 8085 Staphylococcus aureus 133 N=c Streptococcus pyogenes W 10 N 3 CH:

20.2 0.1 mol of 2-amino-3-c an uinoxaline-di-N- g y oq The compounds according to the invention can be used oxide (K. Ley, F. Seng, H. Eholzer, R. Nast and R. Schubart, Angew. Chemie 81, 569 (1969)) are suspended in 100 ml. of dimethylformamide, and 15.3 g. (0.1 mol) of phosphorus oxychloride are added dropwise while stirring and cooling in ice. After the dropwise addition, the mixture is stirred for a further hour and the precipitate is then filtered 01f. 23 g. (90% of theory) of the Compound II are obtained in the form of red crystals, which after recrystallization from pyridine melt at 231 C., with decomposition.

Analysis.--C H N O (molecular weight 257): Calculated (percent): C, 56.0; H, 4.3; N, 27.3. Found (percent): C, 56.0; H, 4.5; N, 27.6.

The compounds according to the invention are elfective against Gram-negative and Gram-positive bacteria. Favorable inhibition values are obtained in the plate test (Table 1) against staphylococci and streptococci which are Gram-positive bacteria, and against enterobacteria (for example Escherichia coli, Proteus and Klebsiella) which are Gram-negative bacteria.

TABLE 1 Minimum inhibitory concentration (MIC) in the plate test The medium used had the following composition both in human medicine and in veterinary medicine, for prophylaxis as well as for the treatment of infections caused by bacteria, and especially for the treatment of local infections.

In such treatment, the compounds can be employed per se or as the active agent in pharmaceutical compositions, such as, for example, ointments, creams, pastes, powders, lotions, solutions, emulsions and suspensions.

Suitable pharmaceutical compositions are produced by combining the active agent with a pharmaceutically acceptable, non-toxic, inert, solid, semi-solid or liquid excipient, carrier or solvent, such as, for example, parafiins, vegetable fats and oils (for example groundnut and sesame oil), alcohols (for example ethyl alcohol and glycerol), glycols (for example propylene glycol and polyethylene glycol), emulsifiers (for example non-ionic and anionic emulsifiers, such as polyoxyethylene-fatty acidesters, polyoxyethylene-fatty alcohol-ethers, alkylsulphonates and acrylsulphonates), natural and synthetic rock powders (for example kaoline, talc, chalk, highly dispersed silica or silicates), sugar (for example lactose and glucose). These formulations are produced according to techniques per se known. The therapeutically active compounds are preferably present in the compositions in a concentration of about 0.5 to about 90 percent by weight of the total composition. The concentration of the active agent, the nature of the excipient carrier or solvent and Protease Peptone 10 the frequency of administration are chosen in accordance Veal extract 10 with the type and severity of the illness, as is customary D extwse 2 particularly in the treatment of local inflammations. Ngcl Furthermore, the compounds according to the present Dlsqdlum Phosphate invention can be used for disinfection purposes. acetate The new compounds according to the present invention Adenine Sulphate are particularly suitable for use as fodder additives, for Guarime hydrochlonde example in raising young animals and fatstock, such as Uracll. chicks, cattle and pigs. Their addition to the fodder leads Xanthm to better utilization of the fodder and hence to more rapid Ionagar growth and more rapid increase in weight of the animals.

' 1000 ml. of distilled water.

When added to the fodder, the new compounds also prevent bacterial infections of the animals.

The good efiectiveness of the compounds according to the invention as fodder additives can be seen from the chick fattening experiment described below (Table 2).

Chick fattening experiment The substances, ground with the fodder, were fed to one-day old chicks. The feeding lasted for seven weeks. Table 2 below gives the experimental data for the compound obtainable according to Example 2, for each of the 7 weeks.

TAB LE 2 Ratio of total Total weight Compound from exampleweight increase/ (amount used is in No. of increase control parentheses) Week animals (in g.) (in percent) Control p.p.m.) 0 50 1 40 100. 0 1 50 84 100.0 2 50 248 100. 0 3 50 429 100.0 4 50 607 100.0 5 50 922 100.0 6 50 1, 250 100. 0 7 50 1, 479 100.0

Example 2 (20 p.p.m.) 0 50 41 1 Weight of the one-day old chicks.

What is claimed is: 1. A 4 amino pyrimido (4,5,b) quinoxaline- 5,10-dioxide of the formula:

wherein R is hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms or cycloalkyl of 5 to 7 carbon atoms, said alkyl and said cycloalkyl being unsubstituted or substituted by one or more identical or different moieties selected from the group consisting of hydroxy and alkoxy of 1 to 4 carbon atoms.

2. A compound according to claim 1, wherein R is hydrogen, methyl, ethyl, n-propyl, iso-propyl, butyl, cyclohexyl or B-hydroxy-ethyl.

3. A compound according to claim 1, wherein R is hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, hydroxyl substituted straight or branched chain alkyl of 1 to 4 carbon atoms, or cyclohexyl.

4. The compound according to claim 1, which is (T) HN-CrHu 6. The compound according to claim 1, which is (T) HN-CaH- 7. The compound according to claim 1, which is 8. The compound according to claim 1, which is III 9. The compound according to claim 1, which is O HN-CHr-CHr-OH 1% a 11. The compound according to claim 1, which is 3 i p -L o 12. A process for the production of a compound of claim 1 which comprises reacting quinoxaline-di-N-oxide of the formula:

N\ oN N=CH-N N -L CH: 0

with an amine of the formula R-NHg, wherein R is hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms or cycloalkyl of 5 to 7 carbon atoms, said 9 alkyl and said cycloalkyl being unsubstituted or substituted by one or more identical or different moieties selected from the group consisting of hydroxy and alkoxy of 1 to 4-carbon atoms in an inert diluent, at a temperature in the range of from 20 to 100 C. 13. A process according to claim 12, wherein the temperature is from 40 to 70 C.

14. A process according to claim 12, wherein the diluent is a polar organic solvent, a lower aliphatic alco- 10 hol, a lower alkylnitrile, an ether, or pyridine.

10 References Cited UNITED STATES PATENTS 6/1960 Drvey et a1. 260-250 A 2/ 1972 Seng et a] 260-250 A NICHOLAS S. RIZZO, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R.

260-250 QN; 424--2so 

